Reduced PS Synthesis Disturbs IP3R-Mediated ER Ca2 Homeostasis

Abstract

Regulation of phospholipid composition is essential for cellular homeostasis. Phosphatidylserine (PS) is mainly enriched and plays critical roles in the plasma membrane. Little is known about the importance of PS synthesis for the function of the endoplasmic reticulum (ER), the primary site of PS production. Here we reveal that PS synthase is important for inositol trisphosphate receptor (IP3R)-mediated ER Ca2+ homeostasis. In Drosophila, knockdown of PS synthase impairs mitochondrial function due to mitochondrial Ca2+ overload. The IP3R channel is involved in this process. Modulating the phosphatidylethanolamine-SREBP pathway suppresses the mitochondrial defects. In mammalian cells lacking PS synthase, activation of IP3R elicits long-lasting Ca2+ oscillations, which can be suppressed through elevation of SREBP activity. In cells with a gain-of-function PS synthase mutation associated with Lenz-Majewski syndrome (LMS), IP3R activation induces lower-amplitude Ca2+ transients. Our data suggest that reduced PS synthesis disturbs ER Ca2+ homeostasis, leading to ER and mitochondrial defects, and provide potential insights for treating associated diseases.

Keywords: phosphatidylserine, Ca2+, IP3R, ER, mitochondria